The fact that many compounds having anti-cancer activity are either insoluble or insufficiently stable in water and other biocompatible solvents has become a burden in drug development, and usually delays the drug development. It is estimated that up to 40% of screened pharmaceutical candidate compounds having potential values are denied the entry into the formulation research and development stage due to their poor water-solubility. In addition, 30% of existing drugs are insoluble. Several technologies currently under research and development are intended to solve the problem related to poor solubility of pharmaceutical compounds. Such technologies include a complexant technology for increasing solubility, a nanoparticle technology, a microemulsion technology, a formulation technology for increasing solubility, a fat-soluble or water-soluble prodrug technology, and a new polymer carrier technology and the like.
Camptothecin (20(s)-camptothecin, formula 1, 1) and its derivatives have good anti-tumor activity, and belong to a class of important DNA topoisomerase I (Top I) inhibitors. They can bind to Top I-DNA cleavable complexes to form CPT-Top I-DNA ternary complexes to stabilize the cleavable complexes and lead to apoptosis. However, they fail to enter the clinical stage due to their poor solubility in water and other biocompatible solvents as well as high toxicity. In order to improve the water-solubility and meanwhile retain the anti-tumor property of the parent compounds, many derivatives of camptothecin have been synthesized. However, only the derivatives topotecan (formula 1, 2) and irinotecan (formula 1, 3) are approved by the U.S. Food and Drug Administration to enter the clinical stage and be marketed, which are used to treat ovarian cancer, lung cancer and rectal cancer, respectively. However, topotecan and irinotecan have prominent disadvantages, including short half-life in vivo and high toxic and side effects etc. At present, there are numerous other derivatives of camptothecin in the clinical trial stage.
In addition, E lactone ring in the camptothecin molecule is an essential function moiety for the anti-cancer activity of camptothecin and derivatives thereof, and rapidly opens under a basic or physiological condition to lead to disappearance of the anti-cancer activity (formula 2). It is confirmed by several experiments that there is an equilibrium between the lactone ring structure and the open-ring structure in plasma. Moreover, a human plasma protein preferably binds to the molecule having the open-ring structure, which facilitates the equilibrium to be shifted towards the open-ring form, leads to decrease of the effective plasma concentration of this class of compounds, and thereby reduces the anti-tumor activity thereof

It is also confirmed by further research that the open-ring structure is the cause of adverse side effects, such as bone marrow suppression, vomiting, diarrhea, and the like.

In order to improve the solubility of a drug, technologies such as an emulsion technology, a micelle technology and the like are in widespread use in a formulation of a drug having poor water-solubility or water-insolubility. However, no formulation technology is applicable to camptothecin at present, because of its highly poor solubility in water and organic solvents. Therefore, there is still a need to develop new camptothecin derivatives having both higher anti-cancer activity and better solubility and stability.
The present invention provides a series of novel fat-soluble camptothecin derivatives which have better solubility in biocompatible fat-soluble solvents and can be formulated into pharmaceutical dosage forms by new formulation technologies, such as emulsions, microemulsions, micelles, liposomes, nanoparticles and the like. The novel pharmaceutical compounds of the present application are expected to improve the duration of action (half-life) and efficacy in vivo and reduce side effects thereof.